STUDIES OF DRUGS GIVEN BEFORE ANAESTHESIA XIX: THE OPIATES

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1 Brit. J. Anaesth. (10),, STUDIES OF DRUGS GIVEN BEFORE ANAESTHESIA XIX: THE OPIATES BY J. W. DUNDEE, W. B. LOAN AND J. D. MORRISON SUMMARY Using Ridit analysis, a comparison was made of the overall effects of what are generally considered to be equianalgesic doses of sixteen opiates, with respect to their desired and toxic effects when given as premedication to a standard population. Four mixtures of opiates, the non-opiate diazepam and saline were also included in the analysis. Results with all individual drugs have been previously reported in detail. Under the conditions of this study, pethidine 0 mg, papaveretum 0 mg and even morphine mg are too toxic to warrant their present popularity. More attention should be paid to the use of levorphanol mg, diamorphine mg, methadone mg and oxycodone mg for premedication. These findings may be modified by the concomitant use of atropine or hyoscine. -hyoscine fully justifies its popularity, but its greater efficacy can be explained by its high morphine content and the action of hyoscine. Under appropriate conditions diazepam may be superior to any of the opiates for use in premedication. In two recent publications Loan and colleagues (1) and Morrison and colleagues (1) have described the results of a comprehensive study of natural, semisynthetic and synthetic opiates, given in doses which are generally considered to be equianalgesic. This study was concerned with the desired and toxic effects of these compounds when given as premedication before a standard minor operation carried out with a constant anaesthetic technique. Seventeen opiates, and saline as a placebo, were included in these studies which involved observations in,00 patients. A large amount of data were obtained, necessitating publication of the findings in two parts. Since these do not provide the reader with concise information about the relative merits of these drugs the present survey was undertaken to provide such information. In addition, it includes findings derived from published data on four commercially available opiate-containing mixtures of drugs which are widely used in premedication (Dundee et al., 1; Loan, Dundee and Clarke, 1; Hamilton et al, 1). The non-opiate drug diazepam is also considered because of its promise as a premedicant, and the present evaluation is based on the results obtained from a total of 00 observations with this drug (Haslett, 1; Dundee et al., 10). Altogether the findings from the,00 observations, which are surveyed here, were collected over a period of about seven years. Morrison, Hill and Dundee (1), however, have shown that, with an adequate number of cases in each series, the method of study is sufficiently controlled as to give reproducible results with different observers. No series discussed here contained less than 0 observations. The full list of drugs surveyed and the dosage in which they were used is shown in table I. This does not include phenadoxone (Heptalgin) from the paper of Morrison and associates (1) because this drug is no longer commercially available. It does retain anileridine which is still widely used in North America. In assessing the overall action of premedicants the authors have allocated "efficacy" and "toxicity" scores to the findings recorded 0-0 minutes after administration. The mean score and distribution of scores for each preparation can be used for comparing the effect of different J. W. DUNDEE, MX>., PH.D., F.FJLRX.S.; W. B. LOAN, MJ)., F.F.A.R.C.S.; J. D. MORRISON, M.D., B.SC., F.FAJLC.S.; Department of Anaesthetics, The Queen's University of Belfast, Northern Ireland. Downloaded from at Pennsylvania State University on March, 01

2 STUDIES OF DRUGS GIVEN BEFORE ANAESTHESIA XIX TABLE I Drugs whose action is surveyed here, with dosage and one alternative or trade name (or contents where applicable). Natural alkaloids Morphine Semi-synthetic alkaloids Diamorphine Dihydronjorphinone Dihydrocodeine Oxymorphonc Oxycodon: Other names Heroin Dilaudid DF Numorphan Proladone Synthetic Morphinans and benzmorphinans Levorphanol Dromoran Phenazocine Narphen Pentazocine Fortral Piperidine derivatives Meperidine Anileridine Alidine Phenoperidine Operidine Fentanyl Sublimase Diphenylheptane derivatives Methadone Dipipanone Dextromoramide Mixtures hyoscine Pamergan P0 Non-opiate Physeptone Pipidol Palfium Omnopon Omnoponscopolamine Promethazine Livallorphan Valium Dose (nig) drugs. The authors prefer ridit analysis, in which the effects of different compounds are compared "Relative to an Identified DIsTribution" (Belville, Bross and Howland, 1; Dundee, Nicholl and Moore, 1). The effects of individual drugs might be compared with those of a pharmacologically inactive preparation (saline) but since the object is to identify the "best" opiate for a particular purpose, it seems more reasonable to compare these with the effects of the total opiate series. Mixtures and non-opiates are not included in this identified distribution since they cannot be considered to be equianalgesic with the opiates. Figure 1 shows the results of the ridit analysis of efficacy and toxicity scores of all the preparations, while figure shows a similar comparison of postoperative emetic scores for the drugs when this information is available (this excludes Pamergan P0). Table II summarizes the findings shown in the figures, and lists drugs in rank order with relation to efficacy as a premedicant, to toxicity, and to frequency and severity of postoperative emetic sequelae. Before considering the results of this survey, it must be stressed that: (a) It deals in the main with the use of drugs as premedication and this may not bear any relationship to their use in other circumstances. (b) The studies were carried out in fit patients undergoing minor gynaecological operations. These patients were able to move freely in the pre-operative period and this may have increased the incidence of sickness, dizziness and possibly tachycardia or hypotension as compared with less mobile patients. (c) The operations were short and recovery from anaesthesia was rapid. Again the amount of movement of the patient may have resulted in an appreciably higher incidence of postoperative vomiting and nausea than would follow a more prolonged operation, or the use of an anaesthetic technique from which recovery was prolonged (d) Female subjects are probably more prone to emetic effects of opiates than males. (e) The opiates were given without an antisialogogue and this may have influenced the incidence of pre- and postoperative sickness. Reported studies have demonstrated the efficacy of atropine and hyoscine in reducing these sequelae (Riding, 10; Dundee, Moore and Clarke, 1). Bearing these limitations in mind it is obvious that in general, the more efficacious compounds have the highest toxicity and it is necessary to seek a compromise between these two aspects of drug action. Moreover, in the dosage used here it is difficult to justify the popularity of pethidine 0 mg and papaveretum 0 mg and possibly even morphine mg, as premedicants, because of their toxicity. is probably superior to the other two in so far as it has a rapid onset and short duration of action and, should they occur, side effects will not last as long as after morphine (Dundee, Clarke and Loan, 1). Downloaded from at Pennsylvania State University on March, 01

3 BRITISH JOURNAL OF ANAESTHESIA AVERAGE ROIT OF EFFICACY AVERAGE TOXICITY SCORES TOTAL OPIATES TOTAL OPIATES DIAMORPHNE DIA DIHYDROMORPHINONE DIHYDROCODEINE PETHILORFAN PAPAVERETUM PAPAVERETUM / HYOSCINE PAMERGAN SALINE DIAZEPAM FIG. 1 Average ridit of efficacy and toxicity scores of the drugs surveyed. The total of opiates was taken as "identified distribution". DIHYDROMORPHINONE DHYDROCOO0NE OXYCOOONE OEXTROMORAMIDE AVERAGE RIDIT OF EMETIC SCORES - * 3 ^a PIOO FIG. Average ridit of postoperative emetic scores of the drugs studied. Total of opiates was taken as "identified distribution". Downloaded from at Pennsylvania State University on March, 01 PETHILORFAN PAPAVERETUM nupaveretum/htosctne SALINE DJAZEPAM

4 STUDIES OF DRUGS GIVEN BEFORE ANAESTHESIA XE Relationship to total opiate series Significantly better Better Similar Worse Significantly worse TABLE II Overall survey of efficacy of drugs relative to the total opiate series. Pre-operative effects DlA -hyoscine Pamergan P0 PETHIDINB DlDIPANONE () 1 ( ) ( ) 3 (T) ) () (3 ) ( ( ( ( (13 ( (1 ) (1) 1 (1) 13 (1) 1 (1) 1 (1) 1 (0) (1 ) (] Toxicity AmLERIDINE DlA -hyoscine PENTAZOCDfE Pamergan P0 () () () (1) (3) () () () () () () (1) (13) (1) (1) (1) (1) (1) (1) (0) (1) () Postoperative emetic sequelae AMLERIDINE DlA -hyoscine Classification is based on the results of ridit analysis as described in text with per cent as accepted level of statistical significance, individual drugs (or mixtures) being compared with the pooled data from all the drugs studied. Drugs in capitals are the opiates studied. Open figures show rank order of these relevant to the parameter studied. Drugs in small type are the opiate mixtures and noo-opiates and figures in brackets show rank order of all preparations, in relation to the parameter studied. Oxymorphone and dihydromorphinone arc also unsuitable for the same reason. Taking the opiates alone, it would appear that more attention should be paid to the potential use of levorphanol, diamorphine, methadone, and possibly oxycodone, as premedicants. It is also obvious that the widely used papaveretum-hyoscine combination (Omnopon and Scopolamine) fully justifies its popularity but its superiority over the individual opiates is due to the larger amount of morphine which it contains (Loan, Dundee and Clarke, 1) and to the sedative effect of hyoscine. Pamergan P0 is also a widely used premedicant, but is too toxic to be recommended. If a pethidine-containing premedicant is preferred, then is more soporific than the pure analgesic Although not directly related to the present study, attention is drawn to the favourable rating of the non-opiate tranquillizer diazepam (Valium) in table II. This also deserves further study. Considering the uses of the opiates for the relief of pain it is worth while noting that dipipanone, phenazocine and dex txomoramide are relatively non-soporific and also fairly non-toxic in the dose used here. The potent analgesic, fentanyl, which is widely used for neuroleptanalgesia shows up very poorly in this study and has nothing to recommend it over other drugs. It should be made clear that the high ranking (3) () (1) () () ffl () () () (ID (1) (13) (1) () (1) (1) (1) (1) (1) (0) (1) Downloaded from at Pennsylvania State University on March, 01

5 BRITISH JOURNAL OF ANAESTHESIA of diamorphine (table II) does not apply to its use in other circumstances, where its addiction potential has to be considered. Likewise, the findings from single-dose administration of opiates may be quite different from those of repeated use where the cumulative action of such long acting compounds as methadone or levorphanol has to be considered. REFERENCES Bellville, J. W., Bross, I. D. J., and Howland, W. C (1). A method for the clinical evaluation of anti-emetic agents. Anesthesiology, 0, 3. Dundee, T. W., Clarke, R. S. J., and Loan, W. B. (1). A comparison of the sedative and toxic effects of morphine-pethidine. Lancet,, 1. Haslett, W. H. K., Keilty, S. R., and Pandit, S. K. (10). Studies of drugs given before anaesthesia. XX: -contaimng mixtures. Brit. J. Anaesth., (in press). Moore, )., and Clarke, R. S. J. (1). Studies of drugs given before anaesthesia. V: 0 mg alone and with atropine or hyoscine. Brit. J. Anaesth., 3, 03. Nicholl, R. M., Clarke, R. S. T., Moore, J., and Love, W. J. (1). Studies of drugs given before anaesthesia. VII: -phenothiazine combinations. Brir. J. Anaesth., 3, 01. Moore, J. (1). Studies of drugs given before anaesthesia. Ill: A method for studying their effect on postoperative vomiting and nausea. Brit. J. Anaesth., 3,. Hamilton, R. C, Dundee, J. W., Clarke, R. S. J., Loan, W. B., and Morrison, J. D. (1). Studies of drugs given before anaesthesia. XIII: Pentazocine and other opiate antagonists. Brit. J. Anaesth, 3,. Haslett, W. H. K. (1). A controlled study of diazepam and chlordiazepoxide as premedicant fox a standard operation. Chapter in in Anaesthesia (eds. Knight, P. F., and Burgess, C G.), p. 1. Bristol: Wright. Loan, W. B., Dundee, J. W., and Clarke, R. S. J. (1). Studies of drugs given before anaesthesia. XII: A comparison of papaveretum and morphine. Brir. J. Anaesth., 3, 1. Morrison, J. D., Dundee, J. W., Clarke, R. S. J., Hamilton, R. C, and Brown, S. S. (1). Studies of drugs given before anaesthesia. XVII: The natural and semi-synthetic opiates. Brit. J. Anaesth., 1,. Morrison, J. D., Hill, G. B., and Dundee, J. W. (1). Studies of drugs given before anaesthesia. XV: Evaluation of the method of study after,000 observations. Brit. J. Anaesth., 0, 0. Loan, W. B., Dundee, J. W., McDowell, S. A., and Brown, S. S. (1). Studies of drugs given before anaesthesia. XVIII: Synthetic analgesics. Brit. J. Anaesth.. 1,. Riding, J. E. (I0). Postoperative vomiting. Proc. roy. Soc. Med., 3, 1. ETUDES DES MEDICAMENTS ADMINISTRES AVANT L'ANESTHESIE XIX: LES OPIACES SOMMATRE Une comparaison a l'aide de l'analyse Ridit a iti fake des effets generaux de doses considrees en general Iquianalgesiques de 1 opiaces, par rapport a leur action souhaitee et leurs effets toxiques apres administration comme premedication a une population standard. Quatre melanges d'opiaofe, le non-opiace diazepam et la solution physiologique ont egalement ete inclus dans l'analyse. Les resultats obtenus avec les medicaments individuels ont iti communiques en detail precedemment. 0 mg, papaveretum 0 mg et meme morphine mg sont, dans les conditions de l'essai, trop toxiques pour justifier leur popularity presente. Cn devrait apporter plus d'attention a l'utilisation pour premedication de levorphanol mg, diamorphine mg, methadone mg et oxycodone mg. L'administration simultanee d'atropine ou hyoscine peut modifier ces observations. La popularity de papaveretum-hyoscine est pleinement justifiee et sa plus grande efficacite s'explique par sa concentration elevee de morphine et par l'action dtiyoscine. peut dans des circonstances appropriees fitre superieur comme premedication a n importe quel opiaci. PROFUNGEN VON ARZNEIMTTTELN, DIE ALS PRAMEDIKATION VOR NARKOSEN VERABREICHT WERDEN XIX: DIE OPIATE ZUSAMMENFASSUNG Unter Anwendung der Ridit-Analyse wurde ein Vergleich der Gesamteffekte von allgemein als gleichwertig angesehenen analgetischen Dosen von 1 Opiaten im Hinblkk auf ihre erwilnschten und toiischen Wirkungen durchgefuhrt; dazu wurden diese Substanzen einem reprssentativen Probandenkollektiv als Pramedikation verabreicht. Vier Mischungen von Opiaten, das opiatfreie und cine Salzlosung wurden ebenfalls in die Analyse mit einbezogen. Uber die Prufungsergebnisse mit den einzelnen Wirkstoffen ist bereits fruher in alien Einzelheiten berichtet worden. Unter den bei dieser Studie vorliegenden Bedingungen waren 0 mg Pethidin, 0 mg und selbst mg Morphin zu toxisch, urn ihre derzeitige Beliebtheit zu rechtfertigen. Dagegen sollte die Application von mg Levorphanol, mg Diamorphin, mg Methadon und mg Oxycodon als Pramedikation mehr Anwendung finden. Diese Befunde konnten moglicherweise durch die gleichzeitige Verabreichung von Atropin oder Hyoscin noch modifiziert werden. Die Kombination von -Hyoscin hat ihre Beliebtheit vollkommen gerechtfertigt; ihre grofiere Wirksamkeit kann jedoch durch ihren hohen Morphingehalt und den Effekt von Hyoscin eridfirt werden. Unter den entsprechenden Bedingungen konnte die Verwendung von in der Pramedikation alien Opiaten uberlegen sein. Downloaded from at Pennsylvania State University on March, 01